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NEOPLASIA
From the Department of Infectious Diseases and the
First Department of Internal Medicine, Nagoya University School of
Medicine; Division of Molecular Medicine, Aichi Cancer Center; the
Department of Medicine, Japanese Red Cross Nagoya First Hospital;
Second Department of Internal Medicine, Nagoya City University School
of Medicine, Nagoya, Japan; Department of Medicine, Saiseikai Maebashi
Hospital, Maebashi, Japan; Second Department of Internal Medicine,
Kumamoto University School of Medicine, Kumamoto, Japan; Department of
Hematology, Atomic Disease Institute, Nagasaki University School of
Medicine, Nagasaki, Japan; First Department of Internal Medicine,
Saitama Medical School, Saitama, Japan; Second Department of Medicine,
Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of
Hematology, Tokyo Metropolitan Komagome Hospital; Department of
Hematology, Tokyo Women's Medical University, Tokyo, Japan; Department
of Hematology, Dokkyo University School of Medicine, Tochigi, Japan;
Second Department of Internal Medicine, Chiba University School of
Medicine, Chiba, Japan; Second Department of Medicine, Okayama
University School of Medicine, Okayama, Japan; and Department of
Medicine III, Hamamatsu University School of Medicine, Hamamatsu,
Japan.
Mutations of receptor tyrosine kinases are implicated in the
constitutive activation and development of human malignancy. An
internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3/ITD) is found
in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leukocytosis and a poor prognosis. On the other hand,
mutations of the c-KIT gene, which have been found in mast cell leukemia and AML, are clustered in 2 distinct regions, the JM
domain and D816 within the activation loop. This study was designed to
analyze the mutation of D835 of FLT3, which corresponds to D816 of
c-KIT, in a large series of human hematologic malignancies. Several
kinds of missense mutations were found in 30 of the 429 (7.0%) AML
cases, 1 of the 29 (3.4%) myelodysplastic syndrome (MDS) cases, and 1 of the 36 (2.8%) acute lymphocytic leukemia patients. The D835Y
mutation was most frequently found (22 of the 32 D835 mutations),
followed by the D835V (5), and D835H (1), D835E (1), and D835N (1)
mutations. Of note is that D835 mutations occurred independently of
FLT3/ITD. An analysis in the 201 patients newly diagnosed with AML
(excluding M3) revealed that, in contrast to the FLT3/ITD mutation
(n = 46), D835 mutations (n = 8) were not significantly related to
the leukocytosis, but tended to worsen disease-free survival. All
D835-mutant FLT3 were constitutively tyrosine-phosphorylated and
transformed 32D cells, suggesting these mutations were constitutively
active. These results demonstrate that the FLT3 gene is the
target most frequently mutated to become constitutively active in AML.
(Blood. 2001;97:2434-2439) Class III receptor tyrosine kinases (RTKs),
consisting of FLT3, KIT, FMS, and PDGF receptor, share structural
characteristics such as 5 immunoglobulin-like domains in the
extracellular regions and a juxtamembrane (JM) domain, 2 kinase domains
(TK1 and TK2) separated by a kinase insert (KI) domain, and a
C-terminal domain in intracellular regions.1 Ligand
binding to the extracellular domain of RTK leads to receptor
dimerization, stabilizing a conformation of the catalytic domain with
the activation loop (A-loop) in an open conformation. This conformation
of the active site accommodates adenosine triphosphate (ATP) and
substrate binding, enabling transphosphorylation of the A-loop,
stabilizing the catalytic domain in an active
conformation.2 Receptor dimerization and the subsequent
phosphorylation of tyrosine residues accompanies RTK activation,
followed by induction of multiple intracellular signaling pathways
leading to cell proliferation and activation. Amplification,
overexpression, or somatic mutation of RTK results in increased
receptor signaling, causing tumorigenesis. Several mutations of RTKs
are implicated in the constitutive activation and development of human
malignancy.3
Recently, an internal tandem duplication (ITD) of the JM domain-coding
sequence of the FLT3 gene (FLT3/ITD) was
found.4 This is present in about 20% of patients with
adult acute myeloid leukemia (AML) and in about 3% of those with
myelodysplastic syndrome (MDS); it is strongly associated with the
leukocytosis and poor prognosis in AML patients.5-12
Although the duplicated sequence varied in both position and length, it
was always in-frame and limited to the JM domain, resulting in an
elongated product. Regardless of the type of ITD, FLT3/ITD mutants are
constitutively dimerized and autophosphorylated on tyrosine residues,
causing the activation of STAT5 and mitogen-activated protein (MAP)
kinase.13,14 In addition, FLT3/ITD-transfected murine
interleukin (IL) 3-dependent cell lines, such as Ba/F3, FDC-P1, and
32D, are able to proliferate without IL-3 and form a blastoma when
inoculated into syngeneic mice.15
In-frame deletion and missense mutations in the c-KIT JM
domain have been identified in mastocytomas and gastrointestinal stromal tumors and shown to cause constitutive activation of the receptor.16 Furthermore, an activating mutation of D816
(single-letter amino acid codes) within the A-loop of c-KIT has been
found in AML cases as well as human mast cell leukemia cell line
HMC-1.17,18 This mutation is thought to cause constitutive
activation by triggering the A-loop into an active conformation. Since
this Asp codon is highly conserved in RTKs, and substitutions to Tyr or
Val in murine c-FMS and murine FLT3 result in constitutive activation
of the receptors,19,20 the Asp within the A-loop is likely
to be a key regulatory residue of the RTKs.
In this study, we first analyzed the mutation of D835 within the A-loop
of FLT3 in a large series of human hematologic malignancies. Next, we
analyzed the clinical characteristics of the AML cases with D835
mutation in comparison with ITD mutation. Finally, we analyzed the
biologic significance of D835 mutation by introducing full-length
mutant FLT3 complementary DNA (cDNA) into Cos7 cells and the
murine IL-3-dependent cell line 32D.
Patients and samples
Reagents and cells
Screening of the ITD and D835 mutation of the FLT3 gene High-molecular-weight DNA was extracted from the samples by the standard method. FLT3/ITD was examined by amplification of the JM domain from exon 11 to 12, followed by electrophoresis on an agarose gel as previously reported.5 To detect mutations at D835, we used the restriction fragment length polymorphism-mediated PCR assay, because D835 and I836 codons were encoded by the nucleotide GATATC, which forms the Eco RV restriction site. We amplified exon 17 of the FLT3 gene by genomic PCR using the primers 17F, 5'-CCGCCAGGAACGTGCTTG-3', and 17R, 5'-GCAGCCTCACATTGCCCC-3', as previously reported.5 Amplified products were digested with Eco RV, and subjected to electrophoresis on an agarose gel (Figure 1). If the amplified products showed the undigested band, it was cut out from the gel, purified with a QIAquick gel extraction kit (Qiagen, Chatsworth, CA), and directly sequenced on a DNA sequencer (310; Applied Biosystems) using a BigDye terminator cycle sequencing kit (Applied Biosystems). In some samples that could not be sequenced directly, Eco RV-undigested fragments were cloned into pT7Blue T-vector (Novagen, Madison, WI) and sequenced.
Construction of the FLT3 mutant Full-length human FLT3 cDNA, kindly provided by Dr Oliver Rosnet (INSERM, France), was recloned into pMKIT-Neo mammalian expression vector, kindly provided by Dr Toshio Kitamura (University of Tokyo, Japan). Mutations of D835, found in clinical samples, were introduced into human wild FLT3 cDNA using the QuikChange Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA) according to the manufacturer's instructions. All constructs were confirmed by sequencing.Phosphorylation analysis of mutant FLT3 The Cos7 cells were transfected with wild-type and mutant FLT3 constructs using LipofectAMINE (Gibco BRL) according to the manufacturer's instructions. After 48 hours of culture, cells were serum starved for 24 to 48 hours before incubation with or without human FL at 50 ng/mL for 10 minutes, and then harvested in lysis buffer as previously described.13 Lysates were immunoprecipitated with rabbit antihuman FLT3 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) and protein G Sepharose (Amersham Pharmacia Biotech, Uppsala, Sweden). The precipitated samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electroblotted onto Immobilon polyvinylidene difluoride (PVDF) membranes (Millipore, Bedford, MA). Immunoblotting was performed with antiphosphotyrosine antibody (4G10; Upstate Biotechnology, Lake Placid, NY). The membranes were incubated with the stripping buffer, then reprobed with anti-FLT3 antibody. Signals were developed by using the enhanced chemoluminescence (ECL) system (Amersham Pharmacia Biotech).Generation of the mutant FLT3-expressing 32D cell lines Wild-type and ITD mutant FLT3-expressing 32D cell lines were reported previously.14,15 The 32D cells were transfected with full-length D835 mutant FLT3 cDNAs cloned in the pMKIT-Neo vector by using TransFast (Promega, Madison, WI), then selected by G418 (Gibco BRL). Expression of FLT3 products was confirmed by flow cytometer (FACSCalibur; Becton Dickinson, San Jose, CA) using an antihuman FLT3 monoclonal antibody (SF1.340; Immunotech, Marseille, France) and Western blotting. Each 32D cell line, which expressed D835 mutant FLT3 stably, was washed 3 times with the RPMI 1640 medium containing 10% FCS, then cultured without IL-3.For cell proliferation assay, 1 × 105 cells were seeded in 24-well culture dishes with or without murine IL-3, and then viable cells were counted daily by trypan blue dye-exclusion assay. Statistical analysis The relationships of clinical characteristics among FLT3 D835 and ITD mutations were analyzed in 201 patients with AML, excluding those with type M3, who were treated with the same therapeutic protocols according to the Japan Adult Leukemia Study Group (JALSG). Differences in median variables in age, peripheral white blood cell (WBC) counts, platelet counts, and serum lactic dehydrogenase (LDH) concentration were analyzed with the Mann-Whitney U test. Analysis of frequencies was performed using the Fisher exact test for 2 × 2 tables or the Pearson 2 test for larger tables.
Survival probabilities were estimated by the Kaplan-Meyer method, and
differences in the survival distributions were evaluated by the
log-rank test. The prognostic significance of the clinical variables
was assessed using the Cox proportional hazards model. These statistic
analyses were performed with StatView-J 5.0 (Abacus Concepts, Berkeley,
CA). For all analyses, the P values were 2-tailed, and a
P value of less than .05 was considered statistically significant.
D835 mutation is found in AML, MDS, and ALL We examined the D835 and ITD mutations of the FLT3 gene in a total of 589 patients with hematologic malignancies (Table 1). We found several kinds of missense mutations of D835 in 30 of the 429 (7.0%) AML, 1 of the 29 (3.4%) MDS, and 1 of the 36 (2.8%) ALL patients. Among AML patients, D835 mutations were found in 7.0% (30 of 429), an incidence significantly lower than that of ITD mutation (81 of 429, 18.9%, P < .001, Fisher exact test). According to the FAB classification, D835 mutation was frequently found in the M5 type (P = .015, Pearson2 test); 1 of 4 (25%) of M0, 2 of 63 (3.1%) of M1, 3 of 99 (3.0%) of M2, 11 of 141 (7.8%) of M3, 4 of 70 (5.7%) of M4, 9 of 40 (22.5%) of M5, 0 of 6 of
M6, and 0 of 6 of M7 cases. In 3 AML patients, whose leukemia cells had
the D835 mutations at the initial diagnosis, the mutations were lost at
the complete remission (CR; Figure 2).
Furthermore, no mutation was found in peripheral blood mononuclear cells from 30 healthy volunteers.
Sequence analysis showed that there were several kinds of D835 mutations, though all were missense. The first nucleotide G of D835 was most frequently substituted with T (22 of the 32 D835 mutations), resulting in an Asp to Tyr amino acid change (D835Y). The T substitution for the second nucleotide A of D835, resulting in an Asp to Val change (D835V), was found in 5 patients. Furthermore, D835H, D835E, and D835N mutations were each found in one patient. Of interest is that D835Y and D835E mutations were found in one AML (M3) patient, whereas cloning analysis showed that these mutations occurred in different alleles. In one MDS (RAEB in T) patient, a different mutation was found at I836. This mutation consisted of the insertion of 3 nucleotides (TTG) between D835 and I836, and AT to GA substitutions at the first and second nucleotides of I836, resulting in insertion of Leu and an Ile to Asp amino acid change (I836L+D). Of note is that both D835 and ITD mutations were found in only one AML (M3) patient. To clarify whether these mutations occurred on the same allele, we amplified the region from JM through TK2 domains by reverse transcriptase-mediated PCR. After Eco RV digestion, the amplified products were separated through a polyacrylamide gel. The result showed that the product with ITD was completely digested by Eco RV but not the product without ITD, suggesting that these mutations occurred on different alleles (data not shown). Clinical characteristics and prognosis of AML patients with or without FLT3 gene mutations Among the AML patients, 201 individuals excluding those with M3 who were treated with the AML87, AML89, and AML92 protocol of the JALSG21-23 were evaluated for their clinical characteristics and initial therapy response (Table 2 and Figure 3). Of these patients, 46 (22.9%) had only an ITD mutation (ITD), 8 (4%) had only a D835 mutation (D835-Mt), and 147 (73.1%) had neither (Wt, wild type). The presence of ITD or D835 mutations was related neither to age, sex, or the occurrence of hepatosplenomegaly or extramedullary involvement, nor to the CR rates for initial induction therapy. WBC counts were significantly higher in the ITD group than the Wt group (P < .0001), whereas those in the D835-Mt and the Wt groups were the same. Serum LDH levels were significantly higher in the ITD group than the Wt group (P = .009), whereas those in the D835-Mt and the Wt groups were the same. The ITD mutation was infrequent in the M2 FAB type (P = .0025) and in the leukemia with t(8; 21) (P = .047); there was no significant difference in the incidence of D835 mutation among FAB types and cytogenetic findings.
At a median follow-up time of 50 (3-118) months, 68 of 201 patients (33.8%) were alive. The predicted overall survival (OS) rates at 50 months were 13.1%, 41.7%, and 37.1% in the ITD, D835-Mt, and Wt groups, respectively (Figure 3A). The ITD group had a worse prognosis than the Wt group (P = .0043), whereas the D835-Mt group did not. Disease-free survival (DFS) was further analyzed in 147 patients who achieved CR. The predicted DFS rates at 50 months were 17.5% and 37.8% in the ITD and Wt groups, respectively. The ITD group had a worse DFS than the Wt group (P = .023). In all 6 patients with the D835-Mt, leukemia relapsed within 28 months. However, the difference was not significant (Figure 3B). D835 mutation is an activating mutation We next examined whether the D835 mutations found in this study resulted in constitutive activation of the FLT3 receptor by introduction of the D835 mutant FLT3 cDNAs into Cos7 and 32D cells. The wild-type FLT3 cDNA was introduced as a negative control and the ITD mutant was introduced as a positive control. When transfected into Cos7 cells, all D835 mutants were FL-independently tyrosine phosphorylated as well as the ITD mutant (Figure 4). In addition, we established all D835 mutant-expressing 32D cell lines. Stable expression of mutant FLT3 was confirmed by flow cytometer and Western blotting. After cloning procedures, the clones with the highest expression on their surface were chosen (Figure 5A) and used following analyses. Wild-type FLT3-expressing 32D cells could not proliferate without IL-3 as well as parental and mock-transfected 32D cells. However, all D835 mutant-expressing 32D cells proliferated without either IL-3 or FL at the same level as the ITD mutant-expressing cells (Figure 5B), and the proliferation rates were the same as those with IL-3 (Figure 5C). These results confirmed that the D835 mutations were gain-of-function mutations.
In this study, we analyzed D835 mutations of the FLT3 gene in a large series of hematologic malignancies, because the Asp within the A-loop of RTKs might be a key residue for the receptor activation. Although we found 32 D835 mutations in a total of 589 patients with hematologic malignancy, they were essentially found in AML or MDS patients in accordance with the ITD mutation.6,7 Interestingly, we found D835 mutation in one ALL patient. It was reported that ITD mutation was found in 2 ALL patients whose leukemia cells expressed myeloid antigens.9 However, leukemia cells of our ALL patient had a B-cell precursor phenotype, but did not express myeloid antigens, suggesting that D835 mutation might be involved in lymphoid lineage cells. To exclude the possibility of polymorphism, we also analyzed normal individuals and the patients both at initial diagnosis and at CR. In all normal individuals, no D835 mutation was found. Furthermore, in the patients with D835 mutation at initial diagnosis, the mutation was lost at CR. These results confirmed that D835 mutations of FLT3 are somatic mutations associated with leukemia. The incidence of D835 mutations was significantly lower than that of ITD mutations; both mutations were mainly found in AML. D816 mutations of c-KIT, which are equivalent to D835 of FLT3, were found in many patients with mastocytosis as well as AML.16 Although most of the D816 mutations of c-KIT were an Asp to Val substitution (D816V), the major D835 mutation of FLT3 was an Asp to Tyr substitution (D835Y). Furthermore, although 3 kinds of D816 c-KIT mutations (D816V, D816Y, and D816F) have been found in patients with mastocytosis and AML, D835H, D835E, and D835N mutations of FLT3 were found in addition to D835Y and D835V mutations. However, the mutants found in this study showed constitutive activation of the receptor in accordance with mutant c-KITs, in which the Asp residue was mutated to a series of other amino acids.24 In one patient with AML (M3), 2 kinds of mutations (D835Y and D835E) were found. Cloning analysis demonstrated that these 2 mutations did not occur on the same allele. Likewise, D835 and ITD mutations were found in one patient with AML (M3), but further analyses showed that these mutations occurred on different alleles. These results suggest that continuing mutations of the FLT3 gene seem to occur in leukemia cells. However, this raises the question of whether all kinds of mutations have the same potential functions in leukemia cells. Because it remains unclear whether all mutations have the same kinase activity, and are associated with the same signal-transduction pathway, we could not entirely rule out the possibility that different kinds of mutations are additively or synergistically associated with the progression of leukemia. Clinical characteristics were analyzed in 201 patients with newly diagnosed AML excluding the M3 cases. In contrast to ITD mutations, D835 mutations did not significantly affect any clinical variables or prognosis. However, these results do not indicate whether D835 mutations have an adverse effect on leukemia cells because such a mutation was found in only 8 patients (4%). Indeed, all 6 patients in the D835-Mt group who achieved CR relapsed within 28 months, whereas there was no significant difference from the Wt group. If D835 mutations are not considered, ITD mutations do not become a poor prognostic factor for DFS. However, if D835 mutations are considered, the ITD group had a significantly lower DFS than the Wt group (P = .023). We previously reported that age 60 years or older and cytogenetics data were the strongest unfavorable factors for DFS in a multivariate analysis in these patients.8 We, therefore, analyzed the effect of D835-Mt on DFS in the 101 patients who were under 60 years old and did not have the karyotypic abnormalities associated with poor prognosis, specifically t(9; 22), 11q23 alterations, del(5) or del(7). Among them, 19 patients had an ITD mutation, 5 had a D835 mutation, and 77 had neither. Although the D835-Mt group was too small for statistical analysis, it showed a tendency for a worse prognosis (P = .09). It has been reported that N-RAS gene mutations were found in 10% to 20% of patients with AML and associated with several clinical variables.25,26 Previously, we also reported that N-RAS gene mutations were found in 28 of the same 201 AML patients and associated with leukocytosis.8 However, N-RAS gene mutations were found in only 3 patients with FLT3/ITD and not in patients with D835 mutations, suggesting that N-RAS and FLT3 gene mutations occur independently. Because it has been demonstrated that the MAP kinase pathway is activated by either FLT3 or RAS,10,27 the leukemia clone, in which MAP kinase is activated, seems not to acquire the other mutation. To exclude the effect of N-RAS gene mutations, we reanalyzed the relationship between D835 mutations and clinical variables in 173 patients without N-RAS mutations. However, we found no significant differences in the patients with D835 mutations. To clarify the clinical significance of the FLT3 gene mutations, a larger scale analysis is required. Although D835 mutants were constitutively activated and caused the autonomous proliferation of 32D cells like ITD mutants, it remains to be clarified whether or not the level of kinase activity and signal-transduction pathway are the same between them. In addition, it has been demonstrated that the level of kinase activity differed with the amino acid substituted for the Asp residue (D814 in c-KIT and D802 in c-FMS) within the A-loop of murine c-KIT and c-FMS. In murine c-KIT, all mutants except D814C had an increased amount of tyrosine phosphorylation without ligand stimulation, and D814Y, D814V, D814L, D814I, and D814W mutants, especially, revealed markedly elevated kinase activity.24 In murine c-FMS, D802Q, D802R, and D802G were inactivating mutations, whereas all other mutants were active.19 According to these results, all types of c-KIT or c-FMS mutations, which corresponded to FLT3 D835 mutations found in this study, caused constitutive activation of the receptor, suggesting that D835 mutations have adverse effects on leukemia cells. This is further supported by the report that Tyr and Val substitutions for Asp, which occupy most of the mutations found in this study (27 of 32, 84%), had the strongest kinase activity in c-KIT.24 However, it should be examined whether all D835 mutations found in this study have the same adverse effects on leukemia cells. In conclusion, this study demonstrated novel activating mutations of FLT3 in patients with AML, MDS, and ALL. Because one third of AML patients have a mutation in the FLT3 gene, the aberrant signal transduction pathways from the mutant FLT3 would serve as an important molecular target for treatment.
This study was performed in cooperation with the Leukemia Study Group of the Ministry of Health and Welfare and JALSG. We would like to thank the participating physicians for sending patients' samples: Drs Tohru Kobayashi, Kosei Matsuei, Shin Matsuda, Yasushi Nakayama, Kiyoshi Kitano, Naomichi Arima, Hikaru Kobayashi, Masatomo Takahashi, Hiroshi Morishita, Isao Maekawa, Hiroshi Furuya, Nobuhiko Kimura, Michiko Ogawa, Shigeru Hoshino, Takahiro Okamoto, Junichi Tamura, Shigeki Ohtake, and Shunichi Kumakura. We also thank Dr Kazuhito Yamamoto for technical advice and Ms Yoko Kudo and Ms Yoko Tagawa for secretarial and technical assistance.
Submitted September 7, 2000; accepted December 15, 2000.
Supported by Grants-in-Aid from the Japanese Ministry of Health and Welfare; the Ministry of Education, Science and Culture; Kowa Life Science Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Tokai Science Academy; Foundation for Promotion of Cancer Research in Japan; and Takeda Science Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hitoshi Kiyoi, Department of Infectious Diseases, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan; e-mail: kiyoi{at}med.nagoya-u.ac.jp.
1. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65:1143-1152[CrossRef][Medline] [Order article via Infotrieve]. 2. Weiss A, Sclessinger J. Switching signals on or off by receptor dimerization. Cell. 1998;94:277-280[CrossRef][Medline] [Order article via Infotrieve]. 3. Robertson SC, Tynan JA, Donoghue DJ. RTK mutations and human syndromes. Trends Genet. 2000;16:265-271[CrossRef][Medline] [Order article via Infotrieve]. 4. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911-1918[Medline] [Order article via Infotrieve]. 5. Kiyoi H, Naoe T, Yokota S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia. 1997;11:1447-1452[CrossRef][Medline] [Order article via Infotrieve]. 6. Horiike S, Yokota S, Nakao M, et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia. 1997;11:1442-1446[CrossRef][Medline] [Order article via Infotrieve]. 7. Yokota S, Kiyoi H, Nakao M, et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia. 1997;11:1605-1609[CrossRef][Medline] [Order article via Infotrieve].
8.
Kiyoi H, Naoe T, Nakano Y, et al.
Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.
Blood.
1999;93:3074-3080 9. Xu F, Taki T, Yang HW, et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br J Haematol. 1999;105:155-162[CrossRef][Medline] [Order article via Infotrieve]. 10. Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia. 1999;13:38-43[CrossRef][Medline] [Order article via Infotrieve]. 11. Kondo M, Horibe K, Takahashi Y, et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol. 1999;33:525-529[CrossRef][Medline] [Order article via Infotrieve]. 12. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 2000;14:675-683[CrossRef][Medline] [Order article via Infotrieve]. 13. Kiyoi H, Towatari M, Yokota S, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333-1337[CrossRef][Medline] [Order article via Infotrieve]. 14. Hayakawa F, Towatari M, Kiyoi H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene. 2000;19:624-631[CrossRef][Medline] [Order article via Infotrieve]. 15. Zhao M, Kiyoi H, Yamamoto Y, et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia. 2000;14:374-378[CrossRef][Medline] [Order article via Infotrieve]. 16. Boissan M, Feger F, Guillosson G-G, Arock M. c-Kit and c-kit mutations in mastocytosis and other hematological diseases. J Leukoc Biol. 2000;67:135-148[Abstract].
17.
Beghini A, Peterlongo P, Ripamonti CB, Larizza L.
C-kit mutations in core binding factor leukemias.
Blood.
2000;95:726-727 18. Furitsu T, Tsujimura T, Tono T, et al. Protein identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92:1736-1744. 19. Morley GM, Uden M, Gullick WJ, Dibb NJ. Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation. Oncogene. 1999;18:3076-3084[CrossRef][Medline] [Order article via Infotrieve]. 20. Fenski R, Flesch K, Serve S, et al. Constitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells. Br J Haematol. 2000;108:322-330[CrossRef][Medline] [Order article via Infotrieve]. 21. Ohno R, Kobayashi T, Tanimoto M, et al. Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. AML-87 Study of the Japan Adult Leukemia Study Group. Cancer. 1993;71:3888-3895[CrossRef][Medline] [Order article via Infotrieve]. 22. Kobayashi T, Miyawaki S, Tanimoto M, et al. Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group. J Clin Oncol. 1996;14:204-213[Abstract]. 23. Miyawaki S, Tanimoto M, Kobayashi T, et al. No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group. Int J Hematol. 1999;70:97-104[Medline] [Order article via Infotrieve].
24.
Moriyama Y, Tsujimura T, Hashimoto K, et al.
Role of aspartic acid 814 in the function and expression of c-kit receptor tyrosine kinase.
J Biol Chem.
1996;271:3347-3350
25.
Radich JP, Kopecky KJ, Willman CL, et al.
N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance.
Blood.
1990;76:801-807
26.
Neubauer A, Dodge RK, George SL, et al.
Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia.
Blood.
1994;83:1603-1611 27. Olson MF, Marais R. Ras protein signalling. Semin Immunol. 2000;12:63-73[CrossRef][Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
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  C. Langer, G. Marcucci, K. B. Holland, M. D. Radmacher, K. Maharry, P. Paschka, S. P. Whitman, K. Mrozek, C. D. Baldus, R. Vij, et al. Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., July 1, 2009; 27(19): 3198 - 3204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Meshinchi and F. R. Appelbaum Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia Clin. Cancer Res., July 1, 2009; 15(13): 4263 - 4269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. H. I. M. Hollink, M. M. van den Heuvel-Eibrink, M. Zimmermann, B. V. Balgobind, S. T. C. J. M. Arentsen-Peters, M. Alders, A. Willasch, G. J. L. Kaspers, J. Trka, A. Baruchel, et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia Blood, June 4, 2009; 113(23): 5951 - 5960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Preudhomme, A. Renneville, V. Bourdon, N. Philippe, C. Roche-Lestienne, N. Boissel, N. Dhedin, J.-M. Andre, P. Cornillet-Lefebvre, A. Baruchel, et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder Blood, May 28, 2009; 113(22): 5583 - 5587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Tyner, M. W. Deininger, M. M. Loriaux, B. H. Chang, J. R. Gotlib, S. G. Willis, H. Erickson, T. Kovacsovics, T. O'Hare, M. C. Heinrich, et al. RNAi screen for rapid therapeutic target identification in leukemia patients PNAS, May 26, 2009; 106(21): 8695 - 8700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sun, M. Pedersen, and L. Ronnstrand The D816V Mutation of c-Kit Circumvents a Requirement for Src Family Kinases in c-Kit Signal Transduction J. Biol. Chem., April 24, 2009; 284(17): 11039 - 11047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Reindl, H. Quentmeier, K. Petropoulos, P. A. Greif, T. Benthaus, B. Argiropoulos, G. Mellert, S. Vempati, J. Duyster, C. Buske, et al. CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome Subtypes Clin. Cancer Res., April 1, 2009; 15(7): 2238 - 2247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Fukushima, I. Matsumura, S. Ezoe, M. Tokunaga, M. Yasumi, Y. Satoh, H. Shibayama, H. Tanaka, A. Iwama, and Y. Kanakura FIP1L1-PDGFR{alpha} Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells J. Biol. Chem., March 20, 2009; 284(12): 7719 - 7732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Weisberg, J. Roesel, G. Bold, P. Furet, J. Jiang, J. Cools, R. D. Wright, E. Nelson, R. Barrett, A. Ray, et al. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells Blood, December 15, 2008; 112(13): 5161 - 5170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Marcucci, K. Maharry, M. D. Radmacher, K. Mrozek, T. Vukosavljevic, P. Paschka, S. P. Whitman, C. Langer, C. D. Baldus, C.-G. Liu, et al. Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study J. Clin. Oncol., November 1, 2008; 26(31): 5078 - 5087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Cheng, L. Li, S. H. Cheng, K. M. Lau, N. P. H. Chan, R. S. M. Wong, M. M. K. Shing, C. K. Li, and M. H. L. Ng Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia Blood, October 15, 2008; 112(8): 3391 - 3402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Paschka, G. Marcucci, A. S. Ruppert, S. P. Whitman, K. Mrozek, K. Maharry, C. Langer, C. D. Baldus, W. Zhao, B. L. Powell, et al. Wilms' Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., October 1, 2008; 26(28): 4595 - 4602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Radich Molecular Classification of Acute Myeloid Leukemia: Are We There Yet? J. Clin. Oncol., October 1, 2008; 26(28): 4539 - 4541. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Laubach and A. V. Rao Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly Oncologist, October 1, 2008; 13(10): 1097 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kurokawa, C. Zhao, T. Reya, and S. Kornbluth Inhibition of Apoptosome Formation by Suppression of Hsp90{beta} Phosphorylation in Tyrosine Kinase-Induced Leukemias Mol. Cell. Biol., September 1, 2008; 28(17): 5494 - 5506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591 Clin. Cancer Res., July 15, 2008; 14(14): 4437 - 4445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Nishioka, T. Ikezoe, J. Yang, A. Miwa, T. Tasaka, Y. Kuwayama, K. Togitani, H. P. Koeffler, and A. Yokoyama Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo Blood, May 15, 2008; 111(10): 5086 - 5092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Schlenk, K. Dohner, J. Krauter, S. Frohling, A. Corbacioglu, L. Bullinger, M. Habdank, D. Spath, M. Morgan, A. Benner, et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia N. Engl. J. Med., May 1, 2008; 358(18): 1909 - 1918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Blood, May 1, 2008; 111(9): 4788 - 4796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bullinger, K. Dohner, R. Kranz, C. Stirner, S. Frohling, C. Scholl, Y. H. Kim, R. F. Schlenk, R. Tibshirani, H. Dohner, et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML Blood, May 1, 2008; 111(9): 4490 - 4495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. V. Balgobind, P. Van Vlierberghe, A. M. W. van den Ouweland, H. B. Beverloo, J. N. R. Terlouw-Kromosoeto, E. R. van Wering, D. Reinhardt, M. Horstmann, G. J. L. Kaspers, R. Pieters, et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis Blood, April 15, 2008; 111(8): 4322 - 4328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Weisberg, L. Banerji, R. D. Wright, R. Barrett, A. Ray, D. Moreno, L. Catley, J. Jiang, E. Hall-Meyers, M. Sauveur-Michel, et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells Blood, April 1, 2008; 111(7): 3723 - 3734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Torkamani and N. J. Schork Prediction of Cancer Driver Mutations in Protein Kinases Cancer Res., March 15, 2008; 68(6): 1675 - 1682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Monni, L. Haddaoui, A. Naba, I. Gallais, M. Arpin, P. Mayeux, and F. Moreau-Gachelin Ezrin is a target for oncogenic Kit mutants in murine erythroleukemia Blood, March 15, 2008; 111(6): 3163 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients Blood, March 1, 2008; 111(5): 2527 - 2537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-F. Huang, S.-K. Luo, J. Xu, J. Li, D.-R. Xu, L.-H. Wang, M. Yan, X.-R. Wang, X.-B. Wan, F.-M. Zheng, et al. Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia Blood, March 1, 2008; 111(5): 2854 - 2865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Tyner, D. K. Walters, S. G. Willis, M. Luttropp, J. Oost, M. Loriaux, H. Erickson, A. S. Corbin, T. O'Hare, M. C. Heinrich, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2238 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, F. Racke, B. L. Powell, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood, February 1, 2008; 111(3): 1552 - 1559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. V. Barry, J. J. Clark, J. Cools, J. Roesel, and D. G. Gilliland Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin Blood, December 15, 2007; 110(13): 4476 - 4479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pradhan, Q. T. Lambert, and G. W. Reuther Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor PNAS, November 20, 2007; 104(47): 18502 - 18507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C.H. de Vries, R. W. Stam, P. Schneider, C. M. Niemeyer, E. R. van Wering, O. A. Haas, C. P. Kratz, M. L. den Boer, R. Pieters, and M. M. van den Heuvel-Eibrink Role of mutation independent constitutive activation of FLT3 in juvenile myelomonocytic leukemia Haematologica, November 1, 2007; 92(11): 1557 - 1560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Furuichi, K. Goi, T. Inukai, H. Sato, A. Nemoto, K. Takahashi, K. Akahane, K. Hirose, H. Honna, I. Kuroda, et al. Fms-like Tyrosine Kinase 3 Ligand Stimulation Induces MLL-Rearranged Leukemia Cells into Quiescence Resistant to Antileukemic Agents Cancer Res., October 15, 2007; 67(20): 9852 - 9861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Mead, D. C. Linch, R. K. Hills, K. Wheatley, A. K. Burnett, and R. E. Gale FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia Blood, August 15, 2007; 110(4): 1262 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Dicker, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia Blood, August 15, 2007; 110(4): 1308 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kiyoi, Y. Shiotsu, K. Ozeki, S. Yamaji, H. Kosugi, H. Umehara, M. Shimizu, H. Arai, K. Ishii, S. Akinaga, et al. A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations Clin. Cancer Res., August 1, 2007; 13(15): 4575 - 4582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Peterson, A. Boyapati, E.-Y. Ahn, J. R. Biggs, A. J. Okumura, M.-C. Lo, M. Yan, and D.-E. Zhang Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts Blood, August 1, 2007; 110(3): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Weisberg, A. L. Kung, R. D. Wright, D. Moreno, L. Catley, A. Ray, L. Zawel, M. Tran, J. Cools, G. Gilliland, et al. Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells Mol. Cancer Ther., July 1, 2007; 6(7): 1951 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Bacher, T. Haferlach, W. Kern, C. Haferlach, and S. Schnittger A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia Haematologica, June 1, 2007; 92(6): 744 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Graf, F. Heidel, S. Tenzer, M. P. Radsak, F. K. Solem, C. M. Britten, C. Huber, T. Fischer, and T. Wolfel A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells Blood, April 1, 2007; 109(7): 2985 - 2988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Meshinchi and R. J. Arceci Prognostic Factors and Risk-Based Therapy in Pediatric Acute Myeloid Leukemia Oncologist, March 1, 2007; 12(3): 341 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Piloto, M. Wright, P. Brown, K.-T. Kim, M. Levis, and D. Small Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways Blood, February 15, 2007; 109(4): 1643 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Dohner Implication of the Molecular Characterization of Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 412 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. DeAngelo, R. M. Stone, M. L. Heaney, S. D. Nimer, R. L. Paquette, R. B. Klisovic, M. A. Caligiuri, M. R. Cooper, J.-M. Lecerf, M. D. Karol, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics Blood, December 1, 2006; 108(12): 3674 - 3681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Meshinchi, T. A. Alonzo, D. L. Stirewalt, M. Zwaan, M. Zimmerman, D. Reinhardt, G. J. L. Kaspers, N. A. Heerema, R. Gerbing, B. J. Lange, et al. Clinical implications of FLT3 mutations in pediatric AML Blood, December 1, 2006; 108(12): 3654 - 3661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Corbacioglu, M. Kilic, M.-A. Westhoff, D. Reinhardt, S. Fulda, and K.-M. Debatin Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand-independent growth and is responsive to a synergistic effect of imatinib and rapamycin Blood, November 15, 2006; 108(10): 3504 - 3513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Knapper, A. K. Burnett, T. Littlewood, W. J. Kell, S. Agrawal, R. Chopra, R. Clark, M. J. Levis, and D. Small A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy Blood, November 15, 2006; 108(10): 3262 - 3270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Knapper, K. I. Mills, A. F. Gilkes, S. J. Austin, V. Walsh, and A. K. Burnett The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases Blood, November 15, 2006; 108(10): 3494 - 3503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ikezoe, C. Nishioka, T. Tasaka, Y. Yang, N. Komatsu, K. Togitani, H. P. Koeffler, and H. Taguchi The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol. Cancer Ther., October 1, 2006; 5(10): 2522 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Thiede, S. Koch, E. Creutzig, C. Steudel, T. Illmer, M. Schaich, G. Ehninger, and for the Deutsche Studieninitiative Leukamie (DSIL) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML) Blood, May 15, 2006; 107(10): 4011 - 4020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Piloto, B. Nguyen, D. Huso, K.-T. Kim, Y. Li, L. Witte, D. J. Hicklin, P. Brown, and D. Small IMC-EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces Nonobese Diabetic/Severe Combined Immunodeficient Engraftment of Some Acute Lymphoblastic Leukemia Cell Lines and Primary Leukemic Samples. Cancer Res., May 1, 2006; 66(9): 4843 - 4851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. W. Parcells, A. K. Ikeda, T. Simms-Waldrip, T. B. Moore, and K. M. Sakamoto FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia Stem Cells, May 1, 2006; 24(5): 1174 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Stirewalt, K. J. Kopecky, S. Meshinchi, J. H. Engel, E. L. Pogosova-Agadjanyan, J. Linsley, M. L. Slovak, C. L. Willman, and J. P. Radich Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia Blood, May 1, 2006; 107(9): 3724 - 3726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cairoli, A. Beghini, G. Grillo, G. Nadali, F. Elice, C. B. Ripamonti, P. Colapietro, M. Nichelatti, L. Pezzetti, M. Lunghi, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study Blood, May 1, 2006; 107(9): 3463 - 3468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Reindl, K. Bagrintseva, S. Vempati, S. Schnittger, J. W. Ellwart, K. Wenig, K.-P. Hopfner, W. Hiddemann, and K. Spiekermann Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML Blood, May 1, 2006; 107(9): 3700 - 3707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Shimada, T. Taki, K. Tabuchi, A. Tawa, K. Horibe, M. Tsuchida, R. Hanada, I. Tsukimoto, and Y. Hayashi KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group Blood, March 1, 2006; 107(5): 1806 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Small FLT3 Mutations: Biology and Treatment Hematology, January 1, 2006; 2006(1): 178 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood, January 1, 2006; 107(1): 293 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Lu, R. Levine, W. Tong, G. Wernig, Y. Pikman, S. Zarnegar, D. G. Gilliland, and H. Lodish Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation PNAS, December 27, 2005; 102(52): 18962 - 18967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Van Vlierberghe, J. P. P. Meijerink, R. W. Stam, W. van der Smissen, E. R. van Wering, H. B. Beverloo, and R. Pieters Activating FLT3 mutations in CD4+/CD8- pediatric T-cell acute lymphoblastic leukemias Blood, December 15, 2005; 106(13): 4414 - 4415. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Gale, R. Hills, A. R. Pizzey, P. D. Kottaridis, D. Swirsky, A. F. Gilkes, E. Nugent, K. I. Mills, K. Wheatley, E. Solomon, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia Blood, December 1, 2005; 106(12): 3768 - 3776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Brandts, B. Sargin, M. Rode, C. Biermann, B. Lindtner, J. Schwable, H. Buerger, C. Muller-Tidow, C. Choudhary, M. McMahon, et al. Constitutive Activation of Akt by Flt3 Internal Tandem Duplications Is Necessary for Increased Survival, Proliferation, and Myeloid Transformation Cancer Res., November 1, 2005; 65(21): 9643 - 9650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Suzuki, H. Kiyoi, K. Ozeki, A. Tomita, S. Yamaji, R. Suzuki, Y. Kodera, S. Miyawaki, N. Asou, K. Kuriyama, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia Blood, October 15, 2005; 106(8): 2854 - 2861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Stam, M. L. den Boer, P. Schneider, P. Nollau, M. Horstmann, H. B. Beverloo, E. van der Voort, M. G. Valsecchi, P. de Lorenzo, S. E. Sallan, et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia Blood, October 1, 2005; 106(7): 2484 - 2490. [Abstract] [Full Text] [PDF]
|
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D. T. Bowen, M. E. Frew, R. Hills, R. E. Gale, K. Wheatley, M. J. Groves, S. E. Langabeer, P. D. Kottaridis, A. V. Moorman, A. K. Burnett, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years Blood, September 15, 2005; 106(6): 2113 - 2119. [Abstract] [Full Text] [PDF]
|
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S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295. [Abstract] [Full Text] [PDF]
|
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X. Yang, L. Liu, D. Sternberg, L. Tang, I. Galinsky, D. DeAngelo, and R. Stone The FLT3 Internal Tandem Duplication Mutation Prevents Apoptosis in Interleukin-3-Deprived BaF3 Cells Due to Protein Kinase A and Ribosomal S6 Kinase 1-Mediated BAD Phosphorylation at Serine 112 Cancer Res., August 15, 2005; 65(16): 7338 - 7347. [Abstract] [Full Text] [PDF]
|
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D. E. Lopes de Menezes, J. Peng, E. N. Garrett, S. G. Louie, S. H. Lee, M. Wiesmann, Y. Tang, L. Shephard, C. Goldbeck, Y. Oei, et al. CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia Clin. Cancer Res., July 15, 2005; 11(14): 5281 - 5291. [Abstract] [Full Text] [PDF]
|
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D. S. Krause and R. A. Van Etten Tyrosine Kinases as Targets for Cancer Therapy N. Engl. J. Med., July 14, 2005; 353(2): 172 - 187. [Full Text] [PDF]
|
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C. Choudhary, J. Schwable, C. Brandts, L. Tickenbrock, B. Sargin, T. Kindler, T. Fischer, W. E. Berdel, C. Muller-Tidow, and H. Serve AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations Blood, July 1, 2005; 106(1): 265 - 273. [Abstract] [Full Text] [PDF]
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R. Grundler, C. Miething, C. Thiede, C. Peschel, and J. Duyster FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model Blood, June 15, 2005; 105(12): 4792 - 4799. [Abstract] [Full Text] [PDF]
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K. Bagrintseva, S. Geisenhof, R. Kern, S. Eichenlaub, C. Reindl, J. W. Ellwart, W. Hiddemann, and K. Spiekermann FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L) Blood, May 1, 2005; 105(9): 3679 - 3685. [Abstract] [Full Text] [PDF]
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L. Tickenbrock, J. Schwable, M. Wiedehage, B. Steffen, B. Sargin, C. Choudhary, C. Brandts, W. E. Berdel, C. Muller-Tidow, and H. Serve Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction Blood, May 1, 2005; 105(9): 3699 - 3706. [Abstract] [Full Text] [PDF]
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D. K. Walters, E. P. Stoffregen, M. C. Heinrich, M. W. Deininger, and B. J. Druker RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518 Blood, April 1, 2005; 105(7): 2952 - 2954. [Abstract] [Full Text] [PDF]
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C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF]
|
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J. Schwable, C. Choudhary, C. Thiede, L. Tickenbrock, B. Sargin, C. Steur, M. Rehage, A. Rudat, C. Brandts, W. E. Berdel, et al. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation Blood, March 1, 2005; 105(5): 2107 - 2114. [Abstract] [Full Text] [PDF]
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P. Chen, M. Levis, P. Brown, K.-T. Kim, J. Allebach, and D. Small FLT3/ITD Mutation Signaling Includes Suppression of SHP-1 J. Biol. Chem., February 18, 2005; 280(7): 5361 - 5369. [Abstract] [Full Text] [PDF]
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O. Piloto, M. Levis, D. Huso, Y. Li, H. Li, M.-N. Wang, R. Bassi, P. Balderes, D. L. Ludwig, L. Witte, et al. Inhibitory Anti-FLT3 Antibodies Are Capable of Mediating Antibody-Dependent Cell-Mediated Cytotoxicity and Reducing Engraftment of Acute Myelogenous Leukemia Blasts in Nonobese Diabetic/Severe Combined Immunodeficient Mice Cancer Res., February 15, 2005; 65(4): 1514 - 1522. [Abstract] [Full Text] [PDF]
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W. Fiedler, H. Serve, H. Dohner, M. Schwittay, O. G. Ottmann, A.-M. O'Farrell, C. L. Bello, R. Allred, W. C. Manning, J. M. Cherrington, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease Blood, February 1, 2005; 105(3): 986 - 993. [Abstract] [Full Text] [PDF]
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P. Brown, M. Levis, S. Shurtleff, D. Campana, J. Downing, and D. Small FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression Blood, January 15, 2005; 105(2): 812 - 820. [Abstract] [Full Text] [PDF]
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M. Wadleigh, D. J. DeAngelo, J. D. Griffin, and R. M. Stone After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies Blood, January 1, 2005; 105(1): 22 - 30. [Abstract] [Full Text] [PDF]
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R. M. Stone, D. J. DeAngelo, V. Klimek, I. Galinsky, E. Estey, S. D. Nimer, W. Grandin, D. Lebwohl, Y. Wang, P. Cohen, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412 Blood, January 1, 2005; 105(1): 54 - 60. [Abstract] [Full Text] [PDF]
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K. Y. Chung, G. Morrone, J. J. Schuringa, B. Wong, D. C. Dorn, and M. A. S. Moore Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis Blood, January 1, 2005; 105(1): 77 - 84. [Abstract] [Full Text] [PDF]
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T. Kindler, F. Breitenbuecher, S. Kasper, E. Estey, F. Giles, E. Feldman, G. Ehninger, G. Schiller, V. Klimek, S. D. Nimer, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) Blood, January 1, 2005; 105(1): 335 - 340. [Abstract] [Full Text] [PDF]
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K. W. H. Yee, M. Schittenhelm, A.-M. O'Farrell, A. R. Town, L. McGreevey, T. Bainbridge, J. M. Cherrington, and M. C. Heinrich Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells Blood, December 15, 2004; 104(13): 4202 - 4209. [Abstract] [Full Text] [PDF]
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J. J. Clark, J. Cools, D. P. Curley, J.-C. Yu, N. A. Lokker, N. A. Giese, and D. G. Gilliland Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518 Blood, November 1, 2004; 104(9): 2867 - 2872. [Abstract] [Full Text] [PDF]
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F. Chiara, M.-J. Goumans, H. Forsberg, A. Ahgren, A. Rasola, P. Aspenstrom, C. Wernstedt, C. Hellberg, C.-H. Heldin, and R. Heuchel A Gain of Function Mutation in the Activation Loop of Plateletderived Growth Factor {beta}-Receptor Deregulates Its Kinase Activity J. Biol. Chem., October 8, 2004; 279(41): 42516 - 42527. [Abstract] [Full Text] [PDF]
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P. Brown, S. Meshinchi, M. Levis, T. A. Alonzo, R. Gerbing, B. Lange, R. Arceci, and D. Small Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition Blood, September 15, 2004; 104(6): 1841 - 1849. [Abstract] [Full Text] [PDF]
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J. Jiang, J. G. Paez, J. C. Lee, R. Bo, R. M. Stone, D. J. DeAngelo, I. Galinsky, B. M. Wolpin, A. Jonasova, P. Herman, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML Blood, September 15, 2004; 104(6): 1855 - 1858. [Abstract] [Full Text] [PDF]
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Y. Li, H. Li, M.-N. Wang, D. Lu, R. Bassi, Y. Wu, H. Zhang, P. Balderes, D. L. Ludwig, B. Pytowski, et al. Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody Blood, August 15, 2004; 104(4): 1137 - 1144. [Abstract] [Full Text] [PDF]
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M. Levis, R. Pham, B. D. Smith, and D. Small In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects Blood, August 15, 2004; 104(4): 1145 - 1150. [Abstract] [Full Text] [PDF]
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 R. Luthra and L. J. Medeiros Isothermal Multiple Displacement Amplification: A Highly Reliable Approach for Generating Unlimited High Molecular Weight Genomic DNA from Clinical Specimens J. Mol. Diagn., August 1, 2004; 6(3): 236 - 242. [Abstract] [Full Text]
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J. Chen, I. R. Williams, J. L. Kutok, N. Duclos, E. Anastasiadou, S. C. Masters, H. Fu, and D. G. Gilliland Positive and negative regulatory roles of the WW-like domain in TEL-PDGF{beta}R transformation Blood, July 15, 2004; 104(2): 535 - 542. [Abstract] [Full Text] [PDF]
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E. J. C. Rombouts, B. Pavic, B. Lowenberg, and R. E. Ploemacher Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia Blood, July 15, 2004; 104(2): 550 - 557. [Abstract] [Full Text] [PDF]
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E. Paietta, A. A. Ferrando, D. Neuberg, J. M. Bennett, J. Racevskis, H. Lazarus, G. Dewald, J. M. Rowe, P. H. Wiernik, M. S. Tallman, et al. Activating FLT3 mutations in CD117/KIT+ T-cell acute lymphoblastic leukemias Blood, July 15, 2004; 104(2): 558 - 560. [Abstract] [Full Text] [PDF]
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B. D. Smith, M. Levis, M. Beran, F. Giles, H. Kantarjian, K. Berg, K. M. Murphy, T. Dauses, J. Allebach, and D. Small Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 15, 2004; 103(10): 3669 - 3676. [Abstract] [Full Text] [PDF]
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S. A. Armstrong, M. E. Mabon, L. B. Silverman, A. Li, J. G. Gribben, E. A. Fox, S. E. Sallan, and S. J. Korsmeyer FLT3 mutations in childhood acute lymphoblastic leukemia Blood, May 1, 2004; 103(9): 3544 - 3546. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
